Conventional photodynamic therapy (PDT) generally involves the administration of a photosensitizer drug or compound to a recipient, either locally or systemically, followed by irradiation with light that is capable of being absorbed by the photosensitizer in the tissue or organ to be treated. The mode of photosensitizer drug delivery is of paramount importance. The drug not only has to be in a form suitable for administration, but also in a form that can readily undergo cellular internalization at the target site, preferably with some degree of selectivity over normal tissues.
There are multiple means of delivering pharmaceutical agents. These range from simple intravenous injection of solutions, emulsions, liposomes and microspheres to complex implantable time-release carriers. Photofrin® (QLT PhotoTherapeutics Inc., Vancouver, B.C., Canada, QLT) has been delivered successfully as part of a simple aqueous solution. Such aqueous solutions may not be suitable for hydrophobic photosensitizer drugs of interest that have a tetra- or poly-pyrrole-based structure. These drugs have an inherent tendency to aggregate by molecular stacking, which can severely curtail subsequent photosensitization processes (Siggel et al. J. Phys. Chem. 100(12):2070-2075, December 1996). One approach for maintaining lipid soluble (hydrophobic) drugs in non-aggregated form is to formulate them in a hydrophobic liposomal bilayer.
Liposomal formulations of some hydrophobic photosensitizing drugs, such as benzoporphyrin derivative monoacid-A (BPD-MA, Verteporfin®, QLT, Vancouver, Canada) and zinc phthalocyanine (CIBA-Geigy Ltd., Basel, Switzerland) are known. The liposome in the case of BPD-MA acts as a passive delivery agent, transferring the photosensitizer to plasma lipoproteins, such as low density lipoproteins (LDL), immediately upon injection into the blood stream. The higher surface expression of LDL receptors in rapidly proliferating tissues affords a level of selectivity to localization of hydrophobic LDL associated drugs at target sites for PDT. Though liposomal formulations have been successfully used for BPD-MA, they have been found unsatisfactory for other, newer photosensitizers developed for PDT in terms of drug loading, formulation stability and in vivo drug delivery. These photosensitizers are hydrophobic in nature and have properties that promote considerably greater molecular stacking interactions; thus, drug aggregation was found to take place even within the liposomal bilayer.
Biocompatible block copolymers are receiving increasingly wider usage in the pharmaceutical industry to enhance drug solubility and bioavailability (reviewed by Schmolka, Chapter 10, pp 189-214, in Tarcha (Ed.) Polymers for Controlled Drug Delivery, CRC Press, Boch Raton, Fla., 1991). This usage has included administration of a number of hydrophobic anti-cancer drugs. In the field of PDT, drug delivery using a two step conjugation of block copolymer N-(2-hydroxypropyl)methacrylamide (HPMA) to photosensitizer drug (Peterson et al. Cancer Res. 56(17):3980-3985, 1996) and, additionally, to antibodies (Omelyanenko et al. Int, J. Cancer. 75:600-608, 1998) have been conducted. HPMA conjugated to photosensitizer drugs, adriamycin or meso chlorin e6 (Mce6), and then to antibodies, for homing the drug to cancer cells, were found to be more effective than without the antibodies (Omelyanenko et al. Supra).
In the field of PDT, there is a continuing need for a drug delivery system that is simple, non-toxic, chemically inert, economical and can easily be used for formulating different types of photosensitizers. Requirements for a photosensitizer formulation include not only maintaining the drug in a relatively non-aggregated form, but also to achieve effective delivery to target site. The end-product should ideally have an extended shelf life (preferably as a solid state formulation) and be easy to reconstitute for administration. To prevent embolisms, particle size for a parenteral formulation must not exceed 1 μm. In the event that the formulation should prove to be unstable to autoclaving or gamma-radiation, particle size must be less than 0.2 μm in order to allow filter sterilization. Other requirements for a parenteral formulation include that they are sterile, isotonic, contain non-toxic components (biodegradable or readily excreted) and have physical and chemical stability. The end-product should ideally have an extended shelf life (preferably as a solid state formulation). All formulations, whether parenteral or otherwise, must be easily hydrated or reconstituted and be stable prior to administration and display effective delivery and performance at the target site, preferably with selective localization over normal tissues.